Mutant KRAS is arguably the most significant therapeutic target for the treatment of pancreatic ductal adenocarcinoma (PDAC). PDAC is uniquely defined by an ~100% incidence of oncogenic mutations in KRAS. Though mutations in KRAS are any early initiating event in PDAC progression, substantial evidence validate the importance of mutant KRAS for maintenance of PDAC growth. There has been an intensive effort by the pharmaceutical industry to develop inhibitors of mutant KRAS function, but to date no inhibitors have reached clinical application. As a consequence, Ras effector signaling has moved to the forefront of drug discovery. The best-studied canonical Ras effector is the Raf-Mek-Erk mitogen-activated protein kinase pathway, which includes three very tractable kinases. Until recently, there has been an exclusive targeting of Raf or Mek, with 18 inhibitors targeting these two components in clinical trials. However, when used as monotherapy, they have not shown effectiveness in mutant Ras cancers. This is due to both de novo and acquired resistance mechanisms that lead to reactivation of Erk downstream of the inhibitor block or through mechanisms that render cancer cells less dependent on Erk. I hypothesize that direct inhibition of Erk will be a superior therapy compared to Raf and Mek. My proposal is based on our preliminary studies evaluating a novel Erk1 and Erk2 selective protein kinase inhibitor (SCH77984; Merck) that exhibits more effective anti-tumor activity than Raf or Mek inhibition. However, we also anticipate that resistance mechanisms can arise that cause de novo or inhibitor-selected acquired resistance. Using de novo resistant cells, we applied a kinome siRNA screen and identified 19 kinases that when suppressed caused a 5-fold enhanced sensitivity to SCH77984. These represent candidate targets for combination inhibitor treatment together with SCH77984 for more effective Erk-targeted therapies. Finally, because K-Ras is known to use multiple effectors to drive cancer development, I hypothesize that concurrent inhibition of other effectors may also enhance the anti-tumor activity of SCH772984. I propose studies to determine (1) the role of Erk in PDAC growth, invasion and metastasis, (2) mechanisms of de novo resistance to SCH772984, and finally, (3) whether concurrent suppression of KRAS effector pathways synergistically enhances SCH772984 anti-tumor activity.